Clinical Trial to Evaluate the Efficacy of Vemurafenib in Combination With Cobimetinib (Continuous and Intermittent) in BRAFV600-mutation Positive Patients With Unresectable Locally Advanced or Metastatic Melanoma

Melanoma Clinical Trial

Official title:

A Randomized Phase II Study of Vemurafenib Plus Cobimetinib Continuous Versus Intermittent, in Previously Untreated BRAFV600- Mutation Positive Patients With Unresectable Locally Advanced or Metastatic Melanoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02583516
• Other study ID #: GEM-01-15
• Secondary ID: 2014-005277-36
• Status: Completed
• Phase: Phase 2
• Start date: June 30, 2015
• Est. completion date: September 30, 2019

Study information

• Verified date: July 2019
• Source: Grupo Español Multidisciplinar de Melanoma
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate the efficacy and safety of two different schedules of administration of vemurafenib in combination with cobimetinib (continuous and intermittent) in previously untreated BRAFV600- mutation positive patients with unresectable locally advanced or metastatic melanoma.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 70
• Est. completion date: September 30, 2019
• Est. primary completion date: September 30, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

Disease-Specific Inclusion Criteria:

1. Patients with histologically confirmed melanoma, either unresectable stage IIIc or stage IV metastatic melanoma.

2. Patients must be naïve to treatment for locally advanced unresectable or metastatic disease.

3. Documentation of BRAFV600 mutation-positive status in melanoma tumor tissue.

4. Measurable disease per RECIST v1.1.

5. ECOG performance status of 0 or 1.

6. Additionally, patients to be included in the biomarker sub- study should meet the following criteria:

• Consent to provide archival tissue for biomarker analyses.

• Consent to undergo tumor biopsies.

General Inclusion Criteria:

7. Male or female patient aged major or equal 18 years.

8. Able to participate and willing to give written informed.

9. Life expectancy mayor o igual 12 weeks.

10. Adequate hematologic and end organ function, within 14 days prior to first dose of study drug treatment:

• ANC major or equal 1.5 × 109/L.

• Platelet count major or equal 100 × 109/L.

• Hemoglobin major or equal 9 g/dL.

• Albumin major or equal 2.5 g/dL.

• Bilirubin minor or equal 1.5 × the upper limit of normal (ULN).

• AST, ALT, and alkaline phosphatase minor or equal 3 × ULN, with the following exceptions:

• Patients with documented liver metastases: AST and/or ALT minor or equal 5 × ULN.

• Patients with documented liver or bone metastases alkaline phosphatase minor o equal 5 × ULN.

• Serum creatinine minor o equal 1.5 × ULN or CrCl major or equal 40 mL/min on the basis of measured CrCl from a 24- hour urine collection.

11. Female patients of childbearing potential and male patients with partners of childbearing potential must agree to always use 2 effective forms of contraception during the course of this study and for at least 6 months after completion of study therapy.

12. Negative serum pregnancy test within 10 days prior to commencement of dosing in women of childbearing potential.

13. Absence of any psychological, familial, sociological, or geographical condition that potentially hampers compliance with the study protocol and follow-up after treatment discontinuation schedule.

Exclusion Criteria:

Cancer-Related Exclusion Criteria:

1. History of prior RAF or MEK pathway inhibitor treatment.

2. Palliative radiotherapy within 14 days prior to the first dose of study treatment.

3. Major surgery or traumatic injury within 14 days prior to first dose of study treatment.

4. Active malignancy other than melanoma that could potentially interfere with the interpretation of efficacy measures. Patients with a previous malignancy within the past 3 years are excluded except for patients with resected BCC or SCC of the skin, melanoma in-situ, carcinoma in-situ of the cervix, and carcinoma in-situ of the breast. History of isolated elevation in prostate-specific antigen in the absence of radiographic evidence of metastatic prostate cancer is allowed.

Exclusion Criteria Based on Ocular Function:

5. History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, retinal vein occlusion (RVO), or neovascular macular degeneration.

The risk factors for RVO are listed below. Patients will be excluded if they have the following conditions:

• Uncontrolled glaucoma with intra-ocular pressures > 21 mmHg.

• Serum cholesterol major or equal Grade 2.

• Hypertriglyceridemia major or equal Grade 2.

• Hyperglycemia (fasting) major or equal Grade 2.

Exclusion Criteria Based on Cardiac Function:

6. History of clinically significant cardiac dysfunction, including the following:

• Current unstable angina.

• Symptomatic congestive heart failure of New York Heart Association class 2 or higher.

• History of congenital long QT syndrome or mean (average of triplicate measurements) QTcF > 450 msec at baseline or uncorrectable abnormalities in serum electrolytes (sodium, potassium, calcium, magnesium, phosphorus). If not automated, calculation of QTcF must be done through the following formula: QTcF = (QT interval in ms) / [(60 / heart rate in bpm) )^(1/3)]

• Uncontrolled hypertension major or equal Grade 2 (patients with a history hypertension controlled with anti-hypertensives to minor or equal Grade 1 are eligible).

• Left ventricular ejection fraction (LVEF) below institutional lower limit of normal (LLN) or below 50%.

Exclusion Criteria Based on Central Nervous System Function:

7. Patients with active CNS lesions (including melanomatous meningitis) are excluded. However, patients are eligible if:

• All known CNS lesions have been treated with stereotactic therapy or surgery, AND

• There has been no evidence of clinical and radiographic disease progression in the CNS for major or equal 3 weeks after radiotherapy or surgery.

Whole brain radiotherapy is not allowed, with the exception of patients who have had definitive resection or stereotactic therapy of all radiologically detectable parenchymal brain lesions.

General Exclusion Criteria:

8. Current severe, uncontrolled systemic disease.

9. History of malabsorption or other condition that would interfere with absorption of study drugs.

10. Pregnant or lactating.

11. Unwillingness or inability to comply with study and follow- up procedures.

12. The following foods/supplements are prohibited at least 7 days prior to initiation of and during study treatment:

• St. Johns wort or hyperforin (potent cytochrome P450 CYP3A4 enzyme inducer).

• Grapefruit juice (potent cytochrome P450 CYP3A4 enzyme inhibitor).

Related Conditions & MeSH terms

• Melanoma

Intervention

Drug:
• vemurafenib and cobimetinib
Comparison between different treatment regimens

Locations

Country	Name	City	State
Spain	Hospital Clínic de Barcelona	Barcelona
Spain	Hospital del Mar	Barcelona
Spain	Hospital Universitario Vall d'Hebron	Barcelona
Spain	Hospital General Universitario Santa Lucía	Cartagena	Murcia
Spain	Hospital Universitario Donostia	Donostia - San Sebastián	Guipuzcoa
Spain	Hospital Insular de Gran Canaria	Las Palmas de Gran Canaria
Spain	Hospital Universitario Lucus Augusti	Lugo
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Regional Universitario de Málaga	Málaga
Spain	Hospital Clínico Universitario de Salamanca	Salamanca
Spain	Hospital Universitario Virgen Macarena	Sevilla
Spain	Hospital Universitario de Canarias	Tenerife
Spain	Hospital General Universitario de Valencia	Valencia
Spain	Hospital Universitario Doctor Peset	Valencia
Spain	Hospital Universitario y Politécnico La Fe	Valencia
Spain	Hospital Álvaro Cunqueiro (Complejo Hospitalario Universitario de Vigo)	Vigo
Spain	Hospital Universitario Miguel Servet	Zaragoza

Sponsors (3)

Lead Sponsor	Collaborator
Grupo Español Multidisciplinar de Melanoma	Pivotal S.L., Roche Farma, S.A

Country where clinical trial is conducted

Spain, 

References & Publications (31)

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* Note: There are 31 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	BRAF mutation determination (Translational sub-study)	Analysis of prognostic and predictive value of BRAF mutation in cell-free DNA (cfDNA) samples, and its role in disease evolution monitoring.	Through study completion, up to 42 months
Other	Analysis of resistance mechanisms to the combination of vemurafenib and cobimetinib (Translational sub-study)	Non-invasive monitorization of resistance mechanisms, through selected gene expression cuantification from blood mRNA.	Through study completion, up to 42 months
Other	Analysis of disease's resistance mechanisms (Translational sub-study)	Determination of resistance mechanisms in secuential biopsies of the disease.	Through study completion, up to 42 months
Primary	Progression Free Survival (PFS)		Through study completion, up to 42 months
Secondary	Overall Response Rate (ORR)		Through study completion, up to 42 months
Secondary	Progression Free Survival (PFS) at one and two years		At one and two years
Secondary	Overall Survival (OS) at one and two years		At one and two years
Secondary	Adverse Events (AE) occurrence		Through study completion, up to 42 months
Secondary	Serious Adverse Events (SAE) occurrence		Through study completion, up to 42 months
Secondary	Adverse Events of Special Interest (AESI) occurrence		Through study completion, up to 42 months

External Links

•   Spanish Multidisciplinary Melanoma Group Web